E. Kurrle

Streptococcal bacteremia in adult patients with leukemia undergoing aggressive chemotherapy. A review of 55 cases

SummaryWe reviewed 55 cases of streptococcal bacteremia in adult patients who received cytotoxic chemotherapy for treatment of acute leukemia. Viridans group streptococci were the most frequent species isolated (45 isolates). Hemolytic streptococci (four isolates), pneumococci (three isolates), and enterococci (three isolates) were infrequent. Clinical features of streptococcal bacteremia included fever, upper and lower respiratory infection, respiratory distress syndrome, soft tissue infection, and septic shock. Forty patients who had only streptococci, but no other organisms isolated from their blood, were compared with 36 cases of gram-negative bacillary bacteremia that occurred during the same study period within the same population at risk. The comparison showed that patients with streptococcal bacteremia had more often received high dose cytosine arabinoside as part of their chemotherapy (17 vs. five), had a longer mean duration of fever (11 vs. seven days, p<0.01) needed slightly more days of antibacterial therapy (15 vs. 12 days, p=0.07, not significant), and were more likely to have been treated with newer quinolones for infection prevention (30 vs. eight). No differences between both groups were found for age, underlying disease, remission status, duration of severe granulocytopenia, and number of superinfections. The overall mortality was 18% in streptococcal bacteremia and 17% in gram-negative bacillary bacteremia. Streptococci, especially viridans group streptococci, should now be regarded as frequent causes of serious life-threatening infections following aggressive chemotherapy in patients with hematologic malignancies.ZusammenfassungDie vorliegende Arbeit analysiert 55 Fälle von Streptokokken-Bakteriämie bei erwachsenen Patienten nach aggressiver antileukämischer Chemotherapie. Vergrünende Streptokokken waren die häufigsten Erreger (45 Isolate). Beta-hämolysierende Streptokokken (vier Isolate), Pneumokokken (drei Isolate) und Enterokokken (drei Isolate) waren dagegen eher selten. Klinisch waren die Infektionen gekennzeichnet durch Fieber, Beteiligung des oberen und unteren Respirationstrakts, Weichteilinfektion, durch Atemnotsyndrom und septischen Schock. 40 Patienten, bei denen ausschließlich Streptokokken in der Blutkultur nachgewiesen wurden, wurden verglichen mit 36 Patienten (ausgewählt nach denselben Kriterien) mit gramnegativer bakteriämischer Infektion. Die Gegenüberstellung ergab, daß Patienten mit Streptokokken-Bakteriämien häufiger hochdosiertes Cytosin-Arabinosid erhalten hatten (17 versus fünf Tage), eine längere Fieberdauer hatten (11 versus sieben Tage, P<0.01), etwas länger antibakterielle Therapie benötigten (15 versus zwölf Tage, P=0.07, nicht signifikant) und häufiger mit Fluorochinolonen zur Infektprophylaxe behandelt waren (30 versus acht). Beide Gruppen unterschieden sich nicht hinsichtlich Alter, Grunderkrankung, Dauer der Granulozytopenie und Häufigkeit von Superinfektionen. Die Letalität betrug 18% bei Streptokokken-Bakteriämie und 17% bei Gram-negativer Bakteriämie. Die Untersuchung zeigt, daß Streptokokken, besonders vergrünende Streptokokken, ungewöhnlich häufig unerwartet schwere Infektionen bei Patienten nach antileukämischer Chemotherapie verursachen können.

Prevention of Infection in Acute Leukemia: A Prospective Randomized Study on the Efficacy of Two Different Drug Regimens for Antimicrobial Prophylaxis

SummaryIn a prospective study patients with acute leukemia undergoing remission induction therapy were randomized to receive either a regimen of non-absorbable antimicrobial drugs (colistin and neomycin) or of absorbable and non-absorbable drugs (trimethoprim-sulfamethoxazole [TMP-SMZ] and colistin) for antibacterial prophylaxis. For antifungal prophylaxis patients in both groups were given oral amphotericin B. The proportion of patients without acquired infections and the median of study time to the first acquired infection did not differ significantly between the two treatment groups (p>0.05). Septicemias occurred in nine out of 49 recipients of colistin and neomycin and in one out of 56 patients receiving TMP-SMZ and colistin (p=0.03). Localized infections and fever episodes without proven infections were equally distributed between the two groups. The incidence of febrile days and of days on parenteral antibiotic therapy was significantly lower in the group given TMP-SMZ and colistin (p<0.05). The duration of severe granulocytopenia and thrombocytopenia did not differ significantly between the two groups (p>0.05).ZusammenfassungIn einer randomisierten Studie wurde die Wirksamkeit von zwei Verfahren der Infektionsprophylaxe an Patienten mit akuten Leukämien untersucht. Die Patienten erhielten entweder eine Kombination nicht resorbierbarer Antibiotika (Colistin und Neomycin) oder eine Kombination resorbierbarer und nicht resorbierbarer antimikrobieller Substanzen (Trimethoprim-Sulfamethoxazol [TMP-SMZ] und Colistin). Zur Pilzprophylaxe wurde in beiden Gruppen Amphotericin B oral eingesetzt. Beide Gruppen unterschieden sich nicht signifikant hinsichtlich des Anteils von Patienten mit erworbenen Infektionen und hinsichtlich des Zeitintervalls bis zur ersten erworbenen Infektion (p>0,05). Septikämien traten bei neun von 49 Patienten auf, die Colistin und Neomycin erhielten, aber nur bei einem von 56 Patienten, die mit TMP-SMZ und Colistin behandelt wurden (p=0,03). Lokale Infektionen und Fieberepisoden ohne nachgewiesene Infektionen waren gleich häufig in beiden Gruppen. Die Häufigkeit von Fiebertagen und Tagen, an denen parenterale Antibiotika verabeicht wurden, war in der Gruppe, die TMP-SMZ und Colistin erhielt, signifikant geringer (p<0,05). Kein signifikanter Unterschied fand sich bei der Dauer der schweren Granulozytopenie und Thrombozytopenie (p>0,05).

High risk of streptococcal septicemia after high dose cytosine arabinoside treatment for acute myelogenous leukemia.

SummaryTwenty-nine adult patients with acute myelogenous leukemia AML who received 40 treatment courses with high dose cytosine arabinoside (HD-A), alone or combined with other cytotoxic drugs, for remission induction (RI) or postremission intensive consolidation (IC) were retrospectively analysed for types and severity of infectious complications. In this paper, we report the unusually high rate of streptococcal septicemia in our patients. Of 13 bacteremic infections in a total of 45 infectious episodes, 10 were caused by streptococci (9 viridans streptococci, 1 group B hemolytic streptococcus). Three of them were lethal. After reviewing all documented cases of streptococcal septicemia in the same study period, four additional cases among adult patients with AML were identified. Three of them have had antileukemic chemotherapy without HD-A, while one have had HD-A as a conditioning regimen for bone marrow transplantation. Only three cases were documented to occur in adult patients with AML. Patients treated with HD-A for RI or IC had a significantly lower risk of streptococcal septicemia during previous chemotherapy-associated febrile neutropenic episodes (1/55 vs 10/45;P=0.01). Neither prophylactic regimens including trimethoprim-sulfamethoxazole nor those without it were effective in preventing streptococcal septicemia. Further studies are needed to confirm these data before the value of additional or alternative prophylactic antibiotics is proven necessary.

Antimicrobial Prophylaxis in Acute Leukaemia: Prospective Randomized Study Comparing Two Methods of Selective Decontamination*

SummaryIn a prospective study the efficacy of two regimens for selective decontamination of the digestive tract was studied in patients with acute leukaemia during remission induction therapy. Seventy-eight patients were randomized to receive either a combination of cotrimoxazole, polymyxin B and nystatin (group A) or a combination of nalidixic acid, polymyxin B, neomycin and nystatin. With both regimens the gastrointestinal tract could be decontaminated equally effectively from potential pathogens. In the oropharyngeal region the decontamination from Enterobacteriaceae was significantly better in group A (P<0.01). In both groups less than 10% of the acquired infections were caused by gram-negative bacilli and no gram-negative septicaemia occurred in either group. The median time interval until the first acquired infection was 17 days in group A and 36 days in group B, respectively (P<0.05). It is concluded that regimen A might be more effective than regimen B though both regimens prevent reliably severe gram-negative infections.

Reversible Keimzelltoxizität nach aggressiver Chemotherapie bei Patienten mit Hodentumoren: Ergebnisse einer prospektiven Studie

The impact of aggressive chemotherapy on reproductive and endocrine gonadal function was prospectively studied in 44 patients with germ cell tumors. Diagnostic procedures to determine gonadal toxicity consisted of hormone determinations, semen analyses, interviews with a standardized questionnaire, and gonadal histology. After chemotherapy all patients showed elevated serum levels of follicle-stimulating hormone (FSH) and azoospermia due to germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH levels and sperm density, occurred in 77% of the patients 25-60 months after cessation of chemotherapy. In all patients serum testosterone and luteinizing hormone (LH) values remained within normal limits after therapy indicating resistance of Leydig cells to cytotoxic drugs. Three patients fathered four healthy children after completion of chemotherapy. These data suggest significant reproductive dysfunction in all men treated for germ cell tumors. However, most patients showed late and complete recovery of spermatogenesis. In contrast, endocrine gonadal function was unaffected after chemotherapy in all patients. FSH and LH are feasible markers to assess drug-induced gonadal toxicity.SummaryThe impact of aggressive chemotherapy on reproductive and endocrine gonadal function was prospectively studied in 44 patients with germ cell tumors. Diagnostic procedures to determine gonadal toxicity consisted of hormone determinations, semen analyses, interviews with a standardized questionnaire, and gonadal histology. After chemotherapy all patients showed elevated serum levels of follicle-stimulating hormone (FSH) and azoospermia due to germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH levels and sperm density, occurred in 77% of the patients 25–60 months after cessation of chemotherapy. In all patients serum testosterone and luteinizing hormone (LH) values remained within normal limits after therapy indicating resistance of Leydig cells to cytotoxic drugs. Three patients fathered four healthy children after completion of chemotherapy. These data suggest significant reproductive dysfunction in all men treated for germ cell tumors. However, most patients showed late and complete recovery of spermatogenesis. In contrast, endocrine gonadal function was unaffected after chemotherapy in all patients. FSH and LH are feasible markers to assess drug-induced gonadal toxicity.

Mucormycosis in the immunocompromised host

SummaryWe are presenting two typical case histories of mucormycosis in patients with acute leukaemia which illustrate some of the important features of this infection in compromised hosts. In such patients, mucormycosis is mostly pulmonary or widely disseminated and often has a rapidly fatal course. A microbiological diagnosis from blood or sputum is difficult to establish. Mucormycosis or other fungal infections should be suspected in compromised patients with infections which do not respond to adequate antibiotic therapy.ZusammenfassungAn zwei Kasuistiken von Mucormykose bei Patienten mit akuten Leukämien werden die typischen Symptome und Verläufe dieser Infektion bei infektabwehrgeschwächten Patienten dargestellt. Bei diesen Patienten tritt vorwiegend die pulmonale oder disseminierte Form der Mucormykose auf, die meist rasch tödlich verläuft. Die Diagnose ist schwierig, da ein mikrobiologischer Nachweis aus Sputum oder Blut nur selten gelingt. Der Verdacht auf das Vorliegen einer Mucormykose oder einer anderen Pilzinfektion sollte insbesondere dann aufkommen, wenn bei einem Patienten mit einer Abwehrschwäche eine Infektion auf eine adäquate antibiotische Therapie nicht anspricht.

Ofloxacin for prevention of bacterial infections in granulocytopenic patients.

SummaryWe studied the potential value of oral ofloxacin (200 mg twice daily) for selective decontamination and infection prevention in 40 granulocytopenic patients with acute leukemia, blast crisis of chronic myelogenous leukemia, hairy cell leukemia or severe aplastic anemia. The quality of selective decontamination was acceptable with rapid elimination of Enterobacteriaceae from the alimentary tract, only a slight decrease in concentrations of anaerobes in faeces, and a small number of newly acquired transient (twelve isolates in seven patients) or colonizing (six strains with 28 isolates in four patients) aerobic gram-negative rods andStaphylococcus aureus (one isolate) recovered from 672 surveillance cultures from faeces, oral washings and urine. Two of three patients colonized with ofloxacin-resistantPseudomonas aeruginosa strains developed Pseudomonas infections. A total of twelve acquired infections was observed. Six were microbiologically documented infections, all caused by ofloacin-resistant bacteria (twoP. aeruginosa, twoStaphylococcus epidermidis, oneAerococcus viridans, oneMicrococcus sp.). Tolerance was acceptable with no serious side effects observed. Mean drug concentrations in serum and saliva were comparable to those determined in healthy volunteers and were found to be higher in saliva than in serum. We conclude that ofloxacin may be studied as an effective alternative to trimethoprim-sulfamethoxazole for selective decontamination and infection prevention in severely granulocytopenic patients. Careful monitoring of colonizingPseudomonas spp. with decreased ofloxacin sensitivity, however, seems necessary.ZusammenfassungDer Wert einer Behandlung mit Ofloxacin (2 × 200 mg täglich) für die sogenannte selektive Dekontamination und Infektionsprophylaxe bei Granulozytopenie wurde bei 40 Patienten mit akuter Leukämie, akuter Phase einer CML, Haarzell-Leukämie oder schwerer aplastischer Anämie untersucht. Es kam zu einer akzeptablen Qualität der selektiven Dekontamination mit Elimination von Enterobacteriaceae in der Darmflora und einer nur geringen Verringerung in der Anaerobier-Konzentration im Stuhl. Die Auswertung von 672 Überwachungskulturen aus Rachenspülung, Stuhl und Urin zeigte eine kleine Zahl von neu entdeckten transienten (zwölf Isolate bei sieben Patienten) oder kolonisierenden (sechs Stämme mit 28 Isolaten bei vier Patienten) aeroben gramnegativen Bakterien und vonStaphylococcus aureus (ein Isolat). Zwei von drei Patienten mit Nachweis von kolonisierenden Ofloxacin-resistentenPseudomonas aeruginosa entwickelten Pseudomonas-Infektionen. Insgesamt wurden zwölf erworbene Infektionen beobachtet, davon sechs mikrobiologisch dokumentierte Infektionen, die alle durch Ofloxacin-resistente Erreger hervorgerufen wurden (zweiP. aeruginosa, zweiStaphylococcus epidermidis, einAerococcus viridans, einMicrococcus sp.). Die Verträglichkeit der Behandlung war gut. Schwere Nebenwirkungen traten nicht auf. Die gemessenen Konzentrationen von Ofloxacin in Serum und Speichel waren vergleichbar zwischen Patienten und gesunden Kontrollen. Sie waren im Speichel höher als im Serum. Ofloxacin sollte zur Prophylaxe bakterieller Infektionen bei Granulozytopenie als eine mögliche geeignete Alternative zu Trimethoprim-Sulfamethoxazol weiter untersucht werden. Das Risiko einer Koloniserung durch Ofloxacin-resistente Pseudomonaden muß dabei beachtet werden.

Antimicrobial prophylaxis in neutropenic patients after bone marrow transplantation.

SummaryFourty-one patients with haematological malignancies or severe aplastic anaemia underwent allogeneic or syngeneic bone marrow transplantation and received one of two forms of infection prophylaxis while granulocytopenic: total decontamination in strict reverse isolation (ITD, 26 patients) or selective decontamination of the digestive tract with barrier nursing (SD, 15 patients). The patients were evaluated for infection acquisition, fever days, days on systemic antibiotics and granulocyte transfusions from 48 hours after the beginning of the decontamination procedure until 1,000 granulocytes/µl have been reached. Ten of 26 patients of the ITD group remained free of febrile episodes and infections, whereas all patients of the SD group acquired infections (p < 0.001). During granulocytopenia patients of the ITD group had fewer fever days, were less frequently on systemic antibiotics and received fewer granulocyte transfusions as compared with the SD group. Both methods were obviously very effective in preventing gram-negative infections, infections caused byStaphylococcus aureus and infections due to yeasts or fungi. No death due to infection occurred in either group. However, the data of this study provide evidence that ITD is a more effective antimicrobial prophylaxis in bone marrow transplant recipients than SD.Zusammenfassung41 Patienten mit malignen hämatologischen Systemerkrankungen oder schwerer Panmyelopathie wurden mit einer allogenen oder syngenen Knochenmarktransplantation behandelt und erhielten zur Infektprophylaxe während der Phase der Granulozytopenie entweder eine totale Dekontamination in strikt reverser Isolation (ITD, 26 Patienten) oder eine selektive Dekontamination des Gastrointestinaltraktes mit „barrier nursing“ (SD, 15 Patienten). Die Patienten wurden ausgewertet bezüglich erworbener Infektionen, Fiebertagen, Tagen unter antibiotischer Therapie und dem Bedarf an Granulozytentransfusionen 48 Stunden nach Beginn der Dekontamination bis zum Erreichen von 1000 Granulozyten/µl. Zehn von 26 Patienten mit ITD blieben frei von Fieberepisoden und Infektionen, während alle Patienten mit SD Infektionen entwickelten (p < 0.001). Während der Phase der Granulozytopenie hatten Patienten der Gruppe ITD weniger Fiebertage, waren seltener unter systemischer Antibiotikatherapie und erhielten weniger häufig Granulozytentransfusionen im Vergleich zu Patienten der Gruppe SD. Beide Methoden waren sehr effektiv in der Prophylaxe gramnegativer Infektionen, Infektionen durchStaphylococcus aureus und Pilzinfektionen. In keiner Gruppe trat eine tödliche Infektion auf. Die Ergebnisse dieser Studie zeigen, daß mit ITD im Vergleich zu SD eine effizientere antimikrobielle Prophylaxe bei Patienten mit Knochenmarktransplantation möglich ist.

A multicentre study on intensive induction and consolidation therapy in acute myelogenous leukaemia

E. Kurrle 1, G. Ehninger 2, M. Freund 3, G. HeiP, D. Hoelzer 4, H. Link 3, P.S. Mitrou 4, S. Ohl s, W. Queisser 6, G. Schlimok 7, and H. Wandt 5 Abteilung Innere Mediziu III, Medizinische Universitfitsklinik, D-7900 Ulm, Federal Republic of Germany 2 Abteilung Hfimatologie, Medizinische Universit~tsklinik, D-7400 Ttibingen, Federal Republic of Germany 3 Abteilung H~matologie-Onkologie, Medizinische Hochschule, D-3000 Hannover, Federal Republic of Germany 4 Abteilung H~tmatologie, Zentrum der Inneren Medizin, Universit~t Frankfurt, D-6000 Frankfurt/Main, Federal Republic of Germany 5 5. Medizinische Klinik, Klinikum NOrnberg, D-8500 Nt~rnberg, Federal Republic of Germany 60nkologisches Zentrum, Klinikum Mannheim, D-6800 Mannheim, Federal Republik of Germany 7 2. Medizinische Klinik, Zentralklinikum Augsburg, D-8900 Augsburg, Federal Republic of Germany

A case of preleukemia — Reconstitution of normal marrow function after bone marrow transplantation (BMT) from identical twin

The encouraging results shown with identical twin bone marrow t ransplanta t ion (BMT) performed in cases with hematological malignancies [1] certainly recommends BMT in any pat ient with hematological mal ignancy who has an identical twin [2]. However, the indicat ion for BMT is not so clear-cut in case of preleukemia which may be regarded as a clinical entity with certain characteristic hematological abnormali t ies which may or may not eventually end in leukemia [3]. Up till now, no documented case of successful BMT in a pat ient with preleukemia exists to our knowledge. The following presents the case report of reconst i tut ion of normal bone marrow function in a case of preleukemia who received BMT from his identical twin brother.